1,2-Benzothiazines

ABSTRACT

The present invention relates to substituted-o-hydroxy- omega (methylsulfinyl) acetophenones of the formula I.   wherein Z is an aromatic or heteroaromatic nucleus such as benzene, naphthalene, anthracene, phenanthrene, pyridine, quinoline, isoquinoline, carbazole, benzothiazine, and the like, wherein R1 is halogen, lower alkoxy, hydroxy, acetamino, alkyl, aralkyl, or aryl; R2 is hydrogen, halogen, hydroxy, alkyl, aralkyl, or aryl; or R1 and R2 taken together may form a 1,3dioxole ring. The compounds of the present invention are useful as intermediates for the production of chromones which exhibit anti-allergenic properties.

United States Patent 1191 Von Strandtmann et al.

[ July 1,1975

[ 1,2-BENZOTHIAZINES [75] Inventors: Maximilian Von Strandtmann,

Rockaway; John Shavel, Jr., Mendham; Sylvester Klutchko, Hackettstown; Marvin Cohen, New Milford, all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

22 Filed: July 27,1973

21 Appl. No.2 383,416

Related US. Application Data [62] Division of Ser. No. 174,947, Aug. 25, 1971, Pat. No.

Primary ExaminerJohn M. Ford Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow; Anne M, Kelly [57] ABSTRACT The present invention relates to substituted-ohydroxyw-(methylsulfinyl) acetophenones of the formula I.

wherein Z is an aromatic or heteroaromatic nucleus such as benzene, naphthalene, anthracene, phenanthrene, pyridine, quinoline, isoquinoline, carbazole, benzothiazine, and the like. wherein R, is halogen, lower alkoxy, hydroxy, acetamino, alkyl, aralkyl, or aryl; R is hydrogen, halogen, hydroxy, alkyl, aralkyl. or aryl; or R and R taken together may form a 1,3- dioxole ring. The compounds of the present invention are useful as intermediates for the production of chromones which exhibit anti-allergenic properties.

1 Claim, N0 Drawings 1 1 ,Z-BEN ZOTHIAZIN ES This is a division of application Ser. No. 174,947 filed Aug. 25, 1971 now U.S. Pat. No. 3,801,644.

As used throughout the specification and claims, the term alkyl and the alkyl portion of alkoxy emr braces both straight and branched alkyl radicals containing from 1 to 9 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-amyl, n-hexyl, 2- ethylbutyl, 2,3-dimethylbutyl and the like. The term halogen encompasses fluorine, bromine, chlorine and iodine. The term aryl denotes an aromatic hydrocarbon of 6 to 8 carbon atoms such as phenyl, tolyl and the like. The term aralkyl encompasses alkyl groups in which aryl as previously defined is substituted for a hydrogen atom such as for example benzyl, phenyl, ethyl, and the like. The term acyl means those hydrocarbon carboxylic acids of less than 12 carbon atoms as exemplified by the lower alkanoic acids, e.g., acetic, propionic, butyric, the aryl carboxylic acids, e.g., benzoic and toluic acid and the like.

The applicants had found in perfecting the process for the production of 3-(hydroxymethyl)chromones that an o-hydroxy-w-(methylsulfinyl)acetophenone would serve as an intermediate for their production. This process and products are fully set forth in their copending application Ser. No. 112,765, filed Feb. 4, 1971, abandoned in favor of continuation-in-part application Ser. No. 309,329, filed Nov. 24, 1972, now U.S. Pat. No. 3,798,240. One method of preparing ohydroxy-m'(methylsulfinyl)acetophenone is set forth in the J. Am. Chem. Soc. 85, at page 3413(1963) as part of an article by Becker et al. The method of preparation described therein dissolves potassium-t-butoxide in DMSO and later reacting the resulting product with methyl salicylate. The yield reported was 18% of theory. The same method could be used to produce a variety of o-hydroxy-w-(methylsulfinyl) acetophenones depending on the selection of starting reagents. The article concerns itself simply with the chemistry involved and gives no indication that such materials have any specific use.

Applicants in their present invention have determined that the unsubstituted-o-hydroxy-wmethylsulfinyl acetophenone shown in Becker has no utility for the purposes of the present invention, in that the chromone produced using this compound as an intermediate has no oral anti-allergenic activity and further, when administered interperitoneally produces CNS side effects such as convulsions.

It is an object of the present invention to provide an improved method for the production of o-hydroxy-w- (methylsulfinyl)acetophenones.

It is a further object of the present invention to provide intermediates from which pharmacologically active end compounds may be produced.

Another object of the present invention is to provide a method for the production of o-hydroxy-w-(methylsulfinyl)acetophenones which is of high efficiency.

The process of the present invention may be stated generally as follows:

Sodium hydride which may be used as a dispersion in mineral oil is added to a mixture of DMSO (dimethyl sulfoxide) in an inert organic solvent. The solvent is chosen on the basis of it being inert to the reactants and itshaving a suitable boiling point in view of the temperatures at which the desired reaction takes place. For

the purpose of the present invention, benzene is the preferred inert solvent. DMSO and benzene are placed in a reaction vessel and the vessel is then swept with nitrogen. The mixture is agitated by bubbling the nitrogen through it or by mechanical stirring or shaking. Sodium hydride (57% dispersion in mineral oil) may be added all at once or incremently. The nitrogen atmosphere is maintained above the mixture, the agitation is continued, and the mixture is heated to a temperature in the range of to C for about A of an hour to 1 hour. This is the preferred range of temperature which should not be exceeded by much since temperatures much above this may cause decomposition of the sodium methylsulfinylmethide. If too much heat is added to the system, it may become explosive. Temperatures much lower than the preferred range, while operable decrease the reaction rate excessively. When the reaction is complete, the mixture in the vessel is cooled to about 35C. V

The second part of this process is that wherein an aromatic ester having hydroxy group in the ortho position with respect to the carboxyl group is added to the sodium methylsulfinyl methide in the reaction vessel incremently while stirring or otherwise agitating the mixture. This reaction is exothermic. It is desirable to carry it out at such a rate that the temperature does not rise above 50. The stirring is continued until such time as the temperature falls to about 25, which usually is only a matter of about one-half hour. The reaction mixture is then diluted with ether. A precipitate forms which may be filtered out. The precipitate is washed with dry ether and then dissolved in ice water. The solution is filtered and the filtrate acidified with glacial acetic acid. A precipitate is formed.

The unsubstituted o-hydroxy-w-(methylsulfinyl- )acetophenone produced by this method is white, crystalline, has a melting point of 151 to 153 and is produced in a yield of 88% theory as contrasted with a yield of 18% theory following the procedure described by Becker et al.

This compound when used to prepare the corresponding unsubstituted chromone produced a compound which when screened for anti-allergenic properties showed none when administered orally to laboratory rats but did induce disturbances of the CNS such as convulsions when administered intraperitoneally.

The following examples are set forth by way of exemplification and not by way of limitation:

EXAMPLE 1 CCH SCH 2-l-lydroxy-2-(methylsulfinyl)acetophenone This compound was prepared by reacting, under a stream of nitrogen, a solution of 12.66 g of Nal-l (57%) mineral oil dispersion in a mixture of 50 ml DMSO and 350 ml of benzene with 16.6 g of ethyl salicylate. The NaH, DMSO, benzene mixture was heated at 75 to 80C for 1 hour then cooled to 35. Ethyl salicylate was added with stirring over a period of 2 minutes. The temperature rose to 50. The stirring was continued for 30 minutes by which time the temperature had fallen to Ether was added to bring the total volume of the 5 mixture to 2 liters. A precipitate formed andwas filtered out, washed with dry ether and dissolved in 150 ml of ice water. The solution was filtered and the filtrate acidified with 24 g of glacial acetic acid. The precipitate formed was filtered off, washed with water and recrystallized from absolute ethanol. Product was white, crystalline mp 151-153. Yield of 17.5 g was 88% of theory.

EXAMPLE 2 1 5 C11 CCH iCH 15.11. Found: C, 56.77; H, 5.79; S, 15.03. *Heilbron. Dictionary of Organic Cmpds.. 4th Ed.. Vol. 3, p. 1816.

EXAMPLE 3 0H CH ECH H 2-Hydroxy-5-methoxy-2-(methylsulfinyl)acetophenone. This was prepared by reacting a solution of 4.4 g of NaH (57% oil dispersion) in a mixture of 120 ml of benzene, and 60 ml of DMSO with 5.5 g of methyl 5- methoxy-salicylate* in analogous fashion to 3- hydroxy-2-(methylsulfinyl)-2'-acetonaphthone. The material was recrystallized from abs. ethanol, mp. l5355.5; yield 4 g (58%).

Anal. Calcd. for l(l 1- O S: C. 52.62; H, 5.30; S, 14.05. Found: C, 52.73; H, 5.42; S, 13.82. *Beilstein. 10 386 60 EXAMPLE 4 OH 0011 I E E C11 C11 4 2 -Hydroxy-3 '-methoxy-2-( methylsulfinyl)acetophenone This material was prepared by reacting a solution of 44 g of NaH (57% oil dispersion) in a mixture of 1200 ml ofbenzene, and 600 ml of DMSO with 55 g of methyl 3-methoxysalicylate* in analogous fashion to 3-hydrox-y-2-(methylsulfinyl)2-acetonaphthone. The material was recrystallized from abs. ethanol, mp. 140.5-43.5; yield 46 g (67%).

Anal. Calcd. for C ,H O,S: C, 52.62; H, 5.30; S,

14.05. Found: C, 52.88; H, 5.26; S, 14.27. *Bcilstein, 10, 386.

EXAMPLE 5 OH lllCH E Cll Cll 2-Hydroxy-3 '-isopropyl-2-(methylsulfinyl)acetophenone This was prepared by reacting a solution of 44 g of NaH in a mixture of 600 ml of benzene and 300 ml of DMSO with 58.2 g of methyl 3-isopropylsalicylate* in analogous fashion to 3-hydroxy-2-(methylsulfinyl)-2- acetonaphthone.

The material was recrystallized from Skelly B, m.p. 111-140; yield 27 g (37.5%).

Anal. Calcd. for C H O S: C, 59.97; H, 6.71; S, 1334. Found: C, 59.75; H, 6.74; S, 13.31.

*The ester was prepared by Fisher esterefication of the acid (Beilstein, 10, 271) in anhydrous CH,,OH in presence of dry HCl.

EXAMPLE 5A 2'-hydroxy-2-(methylsulfinyl )-l '-acetonaphthone This was prepared in analogous fashion to 3'- hydroxy-2-(methylsulfinyl)-2'-acetonaphthone, by reacting a solution of 4.4 g of NaH (57% oil dispersion) in a mixture of 60 ml of DMSO and ml of benzene with 6.48 g of ethyl 2-hydroxy-l-naphthoate [1. M. Huusberger, J.A.C.S., 72, 5634 (1950)]. The material was recrystallized from abs. ethanol, m.p. 47.5; yield 3.5 g (49%).

5 Anal. Calcd for C H O S: C, 62.88; H, 4.87; S, 12.91. Found: C, 62.81; H, 4.87; S, 12.98.

EXAMPLE 6 OCH EXAMPLE7 llO CH3SCHZE H CH iC- CH f-CH CH3 CH 2 '-Hydroxy-2-(methylsulfinyl)-5 1,1,3,3-tetramethylbutyl)acetophenone.

This compound was prepared by reacting a solution of 36 g. of Nai-l (57%) in a mixture of 480 ml. of DMSO, and 960 ml. of benzene with 64 g. of methyl (1,1,3,3-tetramethylbutyl)salicylate (prepared by esterification of 5-( 1,1,3,3-tetramethylbutyl)salicylic acid, Aldrich Chem. Co.) in analogous fashion to 3- hydroxy-2-(methylsulfinyl)-2-acetonaphthone. The material was recrystallized from CH CN, mp. 99l0l; yield 20 g. (27%).

Anal. Calcd for C H O S: C, 65.77; H, 8.44; S, 10.33. Found: C, 66.06; H, 8.48; S, 10.58.

EXAMPLE 8 i011 ECU 3 '-Hydroxy-4-[ (methylsulfinyl )acetyl]acetanilide This was prepared by reacting a solution of 35 g of NaH (57% oil suspension) in a mixture of 1 l. of benzene, and 500 ml of DMSO with 50 g of methyl 4- acetamidosalicylate* in analogous fashion to 3- hydroxy-Z-(methylsulfinyl)-2-acetonaphthone.

The material was recrystallized from abs. ethanol, m.p. 19396; yield 24 g (40%).

Anal. Calcd. for C,,H, -,NO,S: C, 51.75; H, 5.13; N,

5.49; S, 12.56.. *Arzeneimittel Forschung, 12, 485 (1962).

EXAMPLE 9 Cll ECU i 3 -chloro-2-hydroxy-2-(methylsulfinyl )acetophenone This was prepared by reacting a solution of 4.4 g of NaH (57%) in a mixture of 60 ml of DMSO and 120 ml of benzene with 5.6 g of methyl 3-chlorosalicylate (Ben, 61, 2565 (1928), Reissert & Cramer) in analogous fashion to 3-hydroxy-2-(methylsulfinyl)-2'- acetonaphthone. The material was recrystallized from abs ethanol, mp. l21-23.5; yield 4 g (57%).

Anal. Calcd for C H ClO S: C, 46.46; H, 3.90; S. 13.78. Found: C, 46.39; H, 3.87; S, 13.74.

EXAMPLE 10 4'-Chloro-2'-hydroxy-2-(methylsulfinyl )acetophenone This material was prepared by reacting a solution of 4.4 g of NaH (57% oil dispersion) in a mixture of 60 ml of DMSO, and 120 ml of benzene with 5.6 g of methyl 4-chlorosalicylate* in analogous fashion to 3-hydroxy- Z-(methylsulfinyl)2'-acetonaphthone. The material was recrystallized from abs. ethanol, mp. l42-44; yield 3 g (43%).

Anal. Calcd for C H ClO S: C, 46.46; H, 3.90; S, 13.78. Found: C, 46.22; H, 3.81; S, 13.71.

*French Patn. M1973.

EXAMPLE 1 l 011 CH QCH E -Chloro-2'-hydroxy-2-( methylsu1finyl)acetophenone.

This was prepared by reacting a solution of 4.4 g of NaH (57% oil dispersion) in a mixture of 120 ml of 5 benzene and 60 ml. of DMSO with 5.6 g of methyl 5- ch1orosa1icylate* in analogous fashion to 3'hydroxy-2- (methylsulfinyl)-2'-acetonaphthone. The material was recrystallized from abs. ethanol, mp. l4447; yield -Bromo-2-hydroxy-2-( methylsulfinyl )acetophenone This was prepared by reacting a solution of 4.4 g of NaH in a mixture of 60 ml of DMSO and 120 ml of benzene with 6.93 g of methyl 5-bromosa1icylate* in analogous fashion to 3'-hydroxy-2-(methylsulfinyl)-2'- acetonaphthone. The material was recrystallized from abs. ethanol, mp. l48-49; yield 5 g (60%).

Anal. Calcd. for C H BrO S: C, 39.01; H, 3.27; S, 11.57. Found: C, 39.26; H, 3.36; S, 11.64 *Aldrich Chem. Co., Milwaukee, Wis.

EXAMPLE 13 011 Br CH EC1I K 3,5-dibromo-2-hydroxy-2-(methylsulfinyl)acetophenone This was prepared by reacting a solution of 4.4 g of NaH (50% oil dispersion) in a mixture of 120 ml of benzene, and ml of DMSO with 9.27 g of methyl 3,5-dibromosalicylate* in analogous fashion to 3'- 6O hydroxy-2-(methylsulfinyl)-2'-acetonaphthone. The material was recrystallized from abs. ethanol, mp. 15454.5; yield 3 g (28%).

Anal. Calcd for C,,H,,Br O;,S: C, 30.36; H, 2.26; Br, 44.89; S, 9.01. Found: C, 30.23; H, 2.32; Br, 44.65; S,

9.26. *Beilstein, 10,

EXAMPLE 14 2-Hydroxy-5 -iodo-2-( methylsulfinyl)acetophenone This was prepared by reacting a solution of 4.4 g of NaH (57% oil dispersion) in a mixture of ml of benzene and 60 ml of DMSO with 8.34 g of methyl 5- iodosalicylate* in analogous fashion to 3-hydroxy-2- (methylsulfinyl)-2-acetonaphthone. The material was recrystallized from abs. ethanol, mp. 143.545; yield 5.5 g (56%).

Anal. Calcd for C H lO S: C, 33.35; H, 2.80; S, 9.89.

Found: C, 33.51; H, 2.79; S, 10.14. *Ann. Chim. (Rome), 57, 607-15 (1967).

EXAMPLE 15 F CCH ZECHB 5 -Fluoro-2'-hydroxy-2-(methylsulfinyl )acetophenone EXAMPLE 16 Cll Cll E OH 2 ,4'-Dihydroxy-2-(methylsulfinyl)acetophenone This was prepared by reacting a solution of 44 g of NaH (57% oil dispersion) in a mixture of 1200 ml of benzene, and 600 ml of DMSO with 50 g of methyl 2,4-dihydroxybenzoate* in analogous fashion to 3- hydroxy-2-(methylsulfinyl)-2-acetonaphthone. The material was recrystallized from abs. ethanol, mp. 17476; yield 18 g (28%).

Anal. Calcd for C9HmO S: C, 50.46; H, 4.70; S, 1

14.97. Found: C, 50.57; H, 4.71; S, 14.81. *Aldrich Chem. Co.

EXAMPLE 17 l i C11, \1 0/ 8-Hydroxy-1,3-dioxolo[4,5-g]quinolin-7-yl(methylsulfinyl)methyl ketone.

This was prepared by reacting a solution of 27.5 g of NaH (57%) in a mixture of 360 ml of DMSO and 720 methylenedioxy-quinoline-3-carboxylate* in analogous fashion to 3 -hydroxy-2-( methylsulfinyl )-2 acetonaphthone. The material was recrystallized from DMF, mp. l.5-203; yield 38 g. (71%) Anal. Calcd for C H NO S: C, 53.24; H, 3.78; S,

10.93. Found: C, 53.51; H, 3.89; S, 10.80. *U.S. Pat. No. 3,287,458

EXAMPLE 18 4-Hydroxy-6,7dimethoxy-3-quinolyl(methylsulfinyl)- methyl ketone.

10.34. *J. Am. Chem. Soc., 68. 1264 (1946).

EXAMPLE 19 on H 7-Fluoro-4-hydroxy-3-quinolyl (methylsulfinyl) methyl ketone (W7655) A mixture of dimethylsulfoxide (120 ml), benzene (200 ml), and 57% sodium hydride mineral oil dispersion (6.2 g, 0.15 mole) was heated at 75 to 80 with stirring under nitrogen until all the solid had dissolved to give a green solution.

Ethyl-4-hydroxy-7-fluoro-3-quinoline carboxylate* (1 1.75 g, 0.05 mole) was added to the ice cold solution of the dimethylsulfoxide anion with vigorous stirring. The reaction mixture was stirred at room temperature ml. of benzene with 47 g of ethyl 4-hydroxy-6,7- i g for 1 hour and poured into a large excess of ether. The yellow insoluble sodium salts were filtered, washed with ether, and dissolved in water. Acidification with acetic acid gave a pink crystalline solid. No further material was obtained by extraction with ethyl acetate. Recrystallization from absolute ethanol gave pure 7-fluoro-4-hydroxy-3-quinolyl (methylsulfinyl)-methyl ketone as pink crystals. mp. 202204; yield, 4.81 g (36%).

Anal. Calcd for C H FNO S: C, 53.93; H, 3.77; N, 5.24; S, 12.00. Found: C, 53.65; H, 3.78; N, 5.31; S,

12.17. *J. Am. Chem. Soc., 69. 371, 374 1947 EXAMPLE 20 E011 SCH 1 '-hydroxy-2-(methylsulfinyl )-2 -acetonaphthone This was prepared by reacting a solution of 1 l g of NaI-l in a mixture of 300 ml of benzene and ml of DMSO with 15 g of ethyl 1-hydroxy-2-naphthoate* in analogous fashion to 3'-hydroxy-2-(methylsulfinyl)-2- acetonaphthone. The material was recrystallized from ethylacetate with the aid of charcoal, mp. 13840; yield 12.5 g (64%).

Anal. Calcd for C ;,H, ,O;,S: C, 62.88; H, 4.87; S, 12.91. Found: C, 63.18; H, 4.91; S, 13.10.

*Ber.. 20, 2700 (1887) 3 -hydroxy-2-(methylsulfinyl )2 '-acet0naphthone To a mixture of 100 ml of benzene, and 60 ml dimethylsulfoxide was added 4.4 g of NaH. The mixture was heated with stirring under a stream of nitrogen on a water bath at ca. 75 for 45 min. The clear solution was cooled to ca. 25 in an ice-bath, the bath removed, and 5.8 g of ethyl 3-hydroxynaphthoate* was added with stirring. The temp. rose to 40. The solution was stirred until the temp. dropped to 25 (45 min.) and was then diluted to 500 ml. with anhyd. ether. The precipitate was filtered off, washed with anhyd. ether, and dissolved in 30 m1 of H 0. The aqueous solution was then adjusted to ca pH 6 in the cold with glacial acetic acid. The precipitate was filtered off, washed with H 0, and recrystallized from abs. ethanol, mp. 93; yield 3.5 g (46%).

Anal. Calcd for C H O S: C, 62.88; H, 4.87; S,

12.91. Found: C, 63.10; H. 4.84; S, 12.96. *Ber. 25, 3635 EXAMPLE 22 on o 3 cu son EXAMPLE 23 2'-5 -dihydroxy-2-(methylsulfinyl )acetophenone EXAMPLE 24 cll aCll 01-1 4-hydroxy-2-methyl-2H- l ,2-benzothiazin-3-yl(methylsulfinyl)methyl ketone-S,S-dioxide This was prepared by reacting 64.8 g of ethyl-4- hydroxy-2H-l ,2-benzothiazin-3-carboxylate l ,1 dioxid'e* with 35 g of NaH 57% suspension in mineral oil) in a mixture of 960 ml of benzene and 480 ml of DMSO in analogous fashion to 3'-hydroxy-2-(methylsulfinyl)- 2'-acetophenone.

The material was recrystallized from CH CN, mp. 160-161C. Yield 47 g (62% of theory).

Anal. Calcd for C H NO S C, 45.70; H, 4.16; N, 4.44; S, 20.33. Found: C, 45.79; H, 3.97; N, 4.29; S, 20.05

*U.S. Pat. No. 3,501,466

EXAMPLE 25 ECU SCH 3 2-'hydroxy-2-(methylsulfinyl)-3 '-phenyl acetophenone This was prepared by reacting a solution of 4.4 g of NaH (57% suspension in mineral oil) in a mixture of 60 ml of dimethyl sulfoxide and ml of benzene with 6.85 g of methyl-3-phenylsalicylate* in analogous fashion to 3'-hydroxy-2-(methy lsulfiny])-2-acetophenone.

The material was crystallized from absolute ethanol mp. 126-128.

Anal. Calcd for C -,H O S: C, 65.67; H, 5.14; S, 1169. Found: C, 65.80; H, 5.09; S, 11.81.

*Sahyun et a1, J.A. Ph. A. Sci. Ed. 45. 277-281 (1956).

Having described our invention, what we desire to secure by Letters Patent is:

l. A compound which is 4-hydroxy-2-methy1-2H-l,2- benzothiazin-3-yl(methylsulfinyl) methyl ketone S,S- dioxide. 

1. A COMPOUND WHICH IS 4-HYDROXY-2-METHYL-2H-1,2-BENZOTHIAZIN-3-YL(METHYLSULFINYL) METHYL KETONE S,S-DIOXIDE. 